Old drugs find new target for treating brain tumor

ScienceDaily (Nov. 18, 2011) — Scientists at the University of California, San Diego School of Medicine and UC San Diego Moores Cancer Center, in collaboration with colleagues in Boston and South Korea, say they have identified a novel gene mutation that causes at least one form of glioblastoma (GBM), the most common type of malignant brain tumor.

The findings are reported in the online edition of the journal Cancer Research.

Perhaps more importantly, the researchers found that two drugs already being used to treat other forms of cancer effectively prolonged the survival of mice modeling this particular form of GBM. That could be good news for at least some GBM patients. More than 9,000 new cases of the disease are diagnosed each year in the United States and effective treatments are limited. The tumors are aggressive and resistant to current therapies, such as surgery, radiation and chemotherapy. The median survival rate for newly diagnosed GBM patients is just 14 months.

Past studies have identified epidermal growth factor receptor (EGFR) as a common genetically altered gene in GBM, though the cause or causes of the alteration is not known. The research team, led by scientists at the Dana-Farber Cancer Institute in Boston, analyzed the GBM genomic database, ultimately identifying and characterizing an exon 27 deletion mutation within the EGFR carboxyl-terminus domain (CTD). An exon is a segment of a DNA or RNA molecule containing information coding for a protein or peptide sequence.

"The deletion mutant seems to possess a novel mechanism for inducing cellular transformation," said Frank Furnari, PhD, associate professor of medicine at the UC San Diego School of Medicine and an associate investigator at the San Diego branch of the Ludwig Institute for Cancer Research.

The study researchers determined that cellular transformation was induced by the previously unknown EGFR CTD deletion mutant, both in vitro and in vivo, and resulted in GBM in the animals. The researchers then turned to testing a pair of approved drugs that target EGFR: a monoclonal antibody called cetuximab and a small molecule inhibitor called erlotinib.

Cetuximab, marketed under the name Erbitux, is currently approved for use in treating metastatic colorectal cancer and squamous cell carcinoma of the head and neck. Erlotinib, marketed under the name Tarceva, is used to treat lung and pancreatic cancers.

Both drugs were found to effectively impair the tumor-forming abilities of oncogenic EGFR CTD deletion mutants. Cetuximab, in particular, prolonged survival of mice with the deletion mutants when compared to untreated control mice.

However, neither cetuximab nor erlotinib is an unabashed success story. The drugs work by binding to sites on the EGFR protein and inhibiting activation, but they are not effective in all cancer patients and produce some adverse side effects, such as rashes and diarrhea.

But Santosh Kesari, MD, PhD, Director of Neuro-Oncology at UC San Diego Moores Cancer Center and the UCSD Department of Neurosciences, and co-corresponding author of the study, said the new study points to a more selective, effective use of the drugs for some patients with GBM.

"In the past when we treated brain cancer patients with these drugs, the response rate was very small," Kesari said. "What we now show is that the tumors with CTD mutations respond best to these EGFR targeted agents. If we knew this beforehand, we might have been able to select patients most likely to respond to these agents. We are now trying to put together a prospective clinical trial to prove this. We would select only patients with these tumor mutations and treat them. This kind of research gets us closer to identifying genetic subtypes, to doing better biomarker-based clinical trials, and to personalizing treatments in brain cancers."

"This is a great example of personalized medicine in action," said Webster Cavenee, PhD, director of the Ludwig Institute at UC San Diego. "UCSD has made a concerted effort in the past few years to develop a first-class brain tumor research and therapy group that includes adult neuro-oncology, neurosurgery, neuropathology and their pediatric equivalents to join with internationally-renowned brain tumor research. This is making UCSD a destination for the very best in brain tumor management."

Co-authors of the study are Jeonghee Cho, Department of Medical Oncology, Dana-Farber Cancer Institute, Center for Cancer Genome Discovery, Boston, MA, Genomic Analysis Center, Samsung Cancer Research Institute, Seoul, Republic of Korea; Sandra Pastorino and Ying S. Chao, Department of Neurosciences, Moores Cancer Center, UC San Diego; Qing Zeng and Xiaoyin Xu, Department of Radiology, Brigham and Women's Hospital, Boston; William Johnson, Dana-Farber Cancer Institute, Center for Cancer Genome Discovery, Boston; Scott Vandenberg, Department of Pathology, UC San Diego; Roel Verhaak, Amit Dutt, Derek Chiang and Yuki Yuza, Department of Medical Oncology, Dana-Farber Cancer Institute and Broad Institute of MIT and Harvard; Andrew Cherniack and Robert C. Onofrio, Broad Institute of MIT and Harvard; Hideo Watanabe and Matthew Meyerson, Department of Medical Oncology, Dana-Farber Cancer Institute, Center for Cancer Genome Discovery and Broad Institute of MIT and Harvard; Jihyun Kwon, Genomic Analysis Center, Samsung Cancer Research Institute.

Funding for this research came, in part, from the National Institutes of Health, the Sontag Foundation Distinguished Scientist Award, James S. McDonnell and the Samsung Cancer Research Institution.

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Scientists measure dream content for the first time: Dreams activate the brain in a similar way to real actions

ScienceDaily (Oct. 28, 2011) — The ability to dream is a fascinating aspect of the human mind. However, how the images and emotions that we experience so intensively when we dream form in our heads remains a mystery. Up to now it has not been possible to measure dream content. Max Planck scientists working with colleagues from the Charité hospital in Berlin have now succeeded, for the first time, in analysing the activity of the brain during dreaming.

They were able to do this with the help of lucid dreamers, i.e. people who become aware of their dreaming state and are able to alter the content of their dreams. The scientists measured that the brain activity during the dreamed motion matched the one observed during a real executed movement in a state of wakefulness.

The research is published in the journal Current Biology.

Methods like functional magnetic resonance imaging have enabled scientists to visualise and identify the precise spatial location of brain activity during sleep. However, up to now, researchers have not been able to analyse specific brain activity associated with dream content, as measured brain activity can only be traced back to a specific dream if the precise temporal coincidence of the dream content and measurement is known. Whether a person is dreaming is something that could only be reported by the individual himself.

Scientists from the Max Planck Institute of Psychiatry in Munich, the Charité hospital in Berlin and the Max Planck Institute for Human Cognitive and Brain Sciences in Leipzig availed of the ability of lucid dreamers to dream consciously for their research. Lucid dreamers were asked to become aware of their dream while sleeping in a magnetic resonance scanner and to report this "lucid" state to the researchers by means of eye movements. They were then asked to voluntarily "dream" that they were repeatedly clenching first their right fist and then their left one for ten seconds.

This enabled the scientists to measure the entry into REM sleep -- a phase in which dreams are perceived particularly intensively -- with the help of the subject's electroencephalogram (EEG) and to detect the beginning of a lucid phase. The brain activity measured from this time onwards corresponded with the arranged "dream" involving the fist clenching. A region in the sensorimotor cortex of the brain, which is responsible for the execution of movements, was actually activated during the dream. This is directly comparable with the brain activity that arises when the hand is moved while the person is awake. Even if the lucid dreamer just imagines the hand movement while awake, the sensorimotor cortex reacts in a similar way.

The coincidence of the brain activity measured during dreaming and the conscious action shows that dream content can be measured. "With this combination of sleep EEGs, imaging methods and lucid dreamers, we can measure not only simple movements during sleep but also the activity patterns in the brain during visual dream perceptions," says Martin Dresler, a researcher at the Max Planck Institute for Psychiatry.

The researchers were able to confirm the data obtained using MR imaging in another subject using a different technology. With the help of near-infrared spectroscopy, they also observed increased activity in a region of the brain that plays an important role in the planning of movements. "Our dreams are therefore not a 'sleep cinema' in which we merely observe an event passively, but involve activity in the regions of the brain that are relevant to the dream content," explains Michael Czisch, research group leader at the Max Planck Institute for Psychiatry.

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The above story is reprinted from materials provided by Max-Planck-Gesellschaft.

Note: Materials may be edited for content and length. For further information, please contact the source cited above.

Journal Reference:

Martin Dresler, Stefan P. Koch, Renate Wehrle, Victor I. Spoormaker, Florian Holsboer, Axel Steiger, Philipp G. Sämann, Hellmuth Obrig, Michael Czisch. Dreamed Movement Elicits Activation in the Sensorimotor Cortex. Current Biology, Published online Oct. 27, 2011 DOI: 10.1016/j.cub.2011.09.029

Note: If no author is given, the source is cited instead.

Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of ScienceDaily or its staff.

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